The DOI matches its Crossref record; 73 of the 74 references it cites were found in a registry or an index.
Hepatic Oxidative Stress Promotes Insulin-STAT-5 Signaling and Obesity by Inactivating Protein Tyrosine Phosphatase N2
Open accessAbstract
Hepatic insulin resistance is a key contributor to the pathogenesis of obesity and type 2 diabetes (T2D). Paradoxically, the development of insulin resistance in the liver is not universal, but pathway selective, such that insulin fails to suppress gluconeogenesis but promotes lipogenesis, contributing to the hyperglycemia, steatosis, and hypertriglyceridemia that underpin the deteriorating glucose control and microvascular complications in T2D. The molecular basis for the pathway-specific insulin resistance remains unknown. Here we report that oxidative stress accompanying obesity inactivates protein-tyrosine phosphatases (PTPs) in the liver to activate select signaling pathways that exacerbate disease progression. In obese mice, hepatic PTPN2 (TCPTP) inactivation promoted lipogenesis and steatosis and insulin-STAT-5 signaling. The enhanced STAT-5 signaling increased hepatic IGF-1 production, which suppressed central growth hormone release and exacerbated the development of obesity and T2D. Our studies define a mechanism for the development of selective insulin resistance with wide-ranging implications for diseases characterized by oxidative stress.
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“Obesity is associated with systemic oxidative stress (43, 44), which promotes insulin resistance (11–18).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [44]
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Cites
Increased oxidative stress in obesity and its impact on metabolic syndrome
Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., Nakayama, O., Makishima, M., Matsuda, M., & Shimomura, I. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21625 · Cited by 5,508
Insulin signalling and the regulation of glucose and lipid metabolism
Saltiel, A. R., & Kahn, C. R. (2001) · Nature · doi:10.1038/414799a · Cited by 5,326
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
DeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · cited 2×
“Compelling evidence links oxidative stress to the promotion of insulin resistance in humans and rodents (Anderson et al., 2009; Furukawa et al., 2004; Houstis et al., 2006), and oxidative stress in the liver exacerbates inflammation and hepatic fibrosis (Paik et al., 2011; Rolo et al., 2012).”
BackgroundMechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
Michael, M. D., Kulkarni, R. N., Postic, C., Previs, S. F., Shulman, G. I., Magnuson, M. A., & Kahn, C. R. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00015-8 · Cited by 1,296
Anderson, E. J., Lustig, M. E., Boyle, K. E., Woodlief, T. L., Kane, D. A., Lin, C.-T., Price, J. W., Kang, L., Rabinovitch, P. S., Szeto, H. H., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37048 · Cited by 1,253
Postic, C., & Girard, J. R. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34275 · Cited by 1,243
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Morbidity and mortality associated with obesity
Abdelaal, M., le Roux, C. W., & Docherty, N. G. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.03.107 · Cited by 1,052
Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC
Grohmann, M., Wiede, F., Dodd, G. T., Gurzov, E. N., Ooi, G. J., Butt, T., Rasmiena, A. A., Kaur, S., Gulati, T., Goh, P. K., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.053 · Cited by 373
Self-citationSTAT proteins in cancer: orchestration of metabolism
Li, Y., Zhang, C., Martincuks, A., Herrmann, A., & Yu, H. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-022-00537-3 · Cited by 305
The JAK / STAT pathway in obesity and diabetes
Gurzov, E. N., Stanley, W. J., Pappas, E. G., Thomas, H. E., & Gough, D. J. (2016) · The FEBS Journal · doi:10.1111/febs.13709 · Cited by 249
Self-citationChattopadhyay, M., Khemka, V., Chatterjee, G., Ganguly, A., Mukhopadhyay, S., & Chakrabarti, S. (2014) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-014-2236-7 · Cited by 143
Metadata
- Authors
- Gurzov, E. N., Tran, M., Fernandez-Rojo, M. A., Merry, T. L., Zhang, X., Xu, Y., Fukushima, A., Waters, M. J., Watt, M. J., Andrikopoulos, S., Neel, B. G., & Tiganis, T.
- Affiliations
- Monash University (AU)
- University Health Network (CA)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Corresponding author
- Tiganis, Tony
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 20
- Issue
- 1
- Pages
- 85-102
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4335267
- OpenAlex
- W2025897821
- Cited by
- 111
- References
- 74
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 13 · 2023: 20 · 2022: 7 · 2021: 10 · 2020: 6 · 2019: 11 · 2018: 5 · 2017: 10 · 2016: 5 · 2015: 6 · 2014: 3
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (26860162)
- National Cancer Institute (R37CA49152, R37CA049152, R01CA049152, P30CA016087)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- hepatic oxidative stress, insulin resistance, STAT5 signaling, PTPN2, TCPTP, obesity, type 2 diabetes, lipogenesis, hepatic steatosis, gluconeogenesis, insulin-like growth factor I, growth hormone
- MeSH terms
- Glutathione Peroxidase GPX1, Animals, Cells, Cultured, Female, Glutathione Peroxidase, Insulin, Insulin-Like Growth Factor I, Liver, Male, Mice, Inbred C57BL, Obesity, Growth Hormone, Signal Transduction, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Hepatocytes, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Diet, High-Fat
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